Histamine is a biogenic amine that exerts its physiological and pathological functions through four G-protein coupled receptors, histamine receptors H1, H2, H3, and H4 (Parsons and Ganellin, Br. J. Pharm., 147:S127-S135, 2006). The roles of the first three receptors in mediating histamine functions have been well characterized: histamine mediates acute allergic responses via histamine H1 receptor (A. S. F. Ash and H. O. Schild, Br. J. Pharmac. Chemother., 27:427-439, 1966), gastric acid secretion via histamine H2 receptors (J. W. Black et al., Nature, 236:385-390, 1972), and controls neurotransmitter release in the central nervous system via histamine H3 receptor (J. M. Arrang et al., Nature, 302:832-837, 1983). Drugs based on histamine H1 or H2 receptors have achieved “block-bluster” status on the market and several therapeutic indications based on histamine H3 receptor inhibition are in different stages of clinical development for various neural disorders. Importantly, histamine has many additional functions in humans that cannot be explained by signaling pathways involving only histamine H1, H2 and/or H3 receptors. For examples, histamine is known to be involved in asthma and in the pruritus associated with atopic dermatitis and chronic idiopathic urticaria, but current anti-H1 and anti-H2 compounds (antagonists of H1 and/or H2 receptor), which are not active against H4 receptor (Thurmond et al., Nature Review Drug Discovery, 7:41-53, 2008), are ineffective in treating these conditions. With the human genome having been almost completely explored, histamine H4 receptor is the last and most likely the only histamine receptor left to account for these remaining functions of histamine.
Histamine has a relatively high affinity for histamine H4 receptor (Kd=10 nM), which was cloned based on sequence homology to histamine H3 receptor (Oda et al., J. Biol. Chem., 275:36781-36786, 2001; Liu et al., Mol. Pharmacol., 59:420-426, 2001; Morse et al., J. Pharmacol. Exp. Ther., 296:1058-1066, 2001; Nguyen et al., Mol. Pharmacol., 59:427-433, 2001; Zhu et al., Mol. Pharmcol., 59:434-441, 2001; O'Reilly et al., J. Recept. Signal Transduct., 22:431-448, 2002). Histamine H4 receptors are predominantly expressed in the cells of hematopoietic origins (Parsons and Ganellin, Br. J. Pharm., 147:S127-S135, 2006). Possible expression of H4 receptors was also reported in selective tissues within both rodent and human central nerve systems (P. Chazot, Eur. Histamine Res. Soc.-37th Ann. Meeting, 2008; Coge et al., Biochem. Biophy. Res. Commun., 284:301-309, 2001) as well as submucous plexus (Breunig et al., J. Physiol., 583:731-742, 2007). In vitro studies indicated that histamine H4 receptor mediates histamine-induced migration of dendritic cells, mast cells and eosinophils (Hofstra et al., J. Pharmacol. Exp. Ther., 305:1212-1221, 2003; Buckland et al., Br. J. Pharmacol., 140:1117-1127, 2003; Ling et al., Br. J. Pharmcol., 142:161-171, 2004; Gutzmer et al., J. Immunol., 174:5224-5232, 2005). In addition, through histamine H4 receptor, histamine can synergize with other chemotactic agents to enhance migration of eosinophils (O'Reilly et al., supra; Buckland et al., supra; Ling et al., supra). These in vitro data clearly point to a role for histamine H4 receptor in inflammation, immune and possibly neurologic responses.
The predicted functions of histamine H4 receptor based on in vitro studies have been borne out in animal models. Using both H4 knockout animals as well as small molecule inhibitors, histamine H4 receptor has been shown to mediate mast cell migration in the trachea of mice after histamine inhalation (Thurmond et al., J. Pharmacol. Exp. Ther., 309:404-413, 204). Histamine H4 receptor has also been shown to play a critical role in a number of different acute and chronic inflammation models, including carrageenan-induced edema (Coruzzi et al., Eur. J. Pharmacol., 563:240-244, 2007), zymosan-induced pleurisy and peritonitis (Thurmond et al., J. Pharmacol. Exp. Ther., 309:404-413, 2004; Takeshita et al., J. Pharmacol. Exp. Ther., 307:1072-1078, 2003), trinitriobenzene sulphonic acid-induced colitis (Varga et al., Eur. J. Pharmacol., 522:130-138, 2005), picryl chloride-induced and 12-o-tetradecannoylphorbol 13-acetate-modified atopic dermatitis (Hirasawa et al., Int. Arch. Allergy Immunol., 148:279-288, 2009), and allergic lung inflammation (Dunford et al., J. Immunol., 176:7062-7070, 2006). Consistent with its expression in the nervous system, histamine H4 receptor was demonstrated to mediate histamine or antigen-specific IgE-induced acute itch responses (Bell et al., Br. J. Pharmcol., 142:374-380; Dunford et al., J. Allergy Clin. Immunol., 119:176-183, 2007) and inhibition of histamine H4 receptor had antinociceptive effects in various pain models (Coruzzi et al., supra; Altenbach et al., WO2008/060766 A2).
Taken together, histamine appears to mediate many immune, inflammatory, and/or neurologic responses through histamine H4 receptor. Accordingly, histamine H4 receptor is an attractive therapeutic target for inflammatory disorders, pruritus, and pain, including rhinitis, asthma, rheumatoid arthritis, atopic dermatitis, idiopathic chronic urticaria, inflammatory pain, and neuropathic pain.
Thus, new or improved agents that modulate (such as antagonizing/inhibiting) histamine H4 receptor are continually needed for developing new and more effective pharmaceuticals to treat histamine H4 receptor-associated conditions or diseases or disorders, such as inflammatory disorders, pruritus, and pain, including rhinitis, asthma, rheumatoid arthritis, atopic dermatitis, idiopathic chronic urticaria, inflammatory pain, and neuropathic pain, to name a few. The compounds, compositions and methods described herein are directed toward these needs and other ends.